AbbVie's recent setback with its muscarinic candidate emraclidine in a pair of Phase II trials has solidified Bristol Myers Squibb's (BMS) position in the schizophrenia treatment landscape. The failure of emraclidine, designed to target the muscarinic pathway, contrasts sharply with the success of BMS's Cobenfy (KarXT), approved by the FDA in September as the first novel schizophrenia drug in 30 years.
The acquisition of Karuna Therapeutics by BMS for $14 billion in December 2023, followed closely by AbbVie's $8.7 billion acquisition of Cerevel Therapeutics, set the stage for a competitive race in the muscarinic space. Muscarinic agonists have garnered attention for their potential to mitigate the adverse effects associated with traditional antipsychotics, such as sedation, movement disorders, and hormonal changes.
Emraclidine's Phase II Trial Results
However, emraclidine failed to achieve statistically significant improvement in schizophrenia symptoms compared to placebo in the EMPOWER-1 and EMPOWER-2 trials. These Phase II trials were considered potentially registrational due to their larger-than-average size. In response to the news, AbbVie's stock experienced a 12% drop, while BMS's shares rose by approximately 11% due to perceived reduced competition for Cobenfy.
Cobenfy's Mechanism and Competitive Advantage
Cobenfy's efficacy in treating schizophrenia has been established in three registrational trials. While the exact mechanism of action of Cobenfy is still under investigation, it targets both M1 and M4 receptors, whereas emraclidine selectively targets M4. Some experts suggest that M1 agonism may contribute to cognitive benefits, potentially giving Cobenfy an advantage.
Other Players in the Schizophrenia Space
Despite AbbVie's setback, other companies are actively pursuing novel treatments for schizophrenia. Neurocrine Biosciences reported positive topline data from a Phase II trial of NBI-1117568, an oral muscarinic M4 selective agonist. A 20-mg dose of NBI-1117568 met the trial's primary endpoint, demonstrating a statistically significant improvement in positive and negative symptoms of schizophrenia at week six, with a placebo-adjusted mean reduction of 7.5 points on the Positive and Negative Syndrome Scale (PANSS). Neurocrine plans to initiate a Phase III trial in early 2025.
Neumora Therapeutics is also advancing a new M4 positive allosteric modulator candidate for schizophrenia, with plans to enter clinical trials in 2025. Additionally, Reviva Pharmaceuticals is developing brilaroxazine, a serotonin-dopamine signaling modulator, while Boehringer Ingelheim and Alto Neuroscience are focusing on addressing the cognitive symptoms of schizophrenia.
BMS's Commanding Position
Currently, BMS holds a significant lead in the schizophrenia treatment space. Cobenfy has a first-mover advantage and is estimated to be at least 2-3 years ahead of its competitors. The failure of AbbVie's emraclidine has further extended this lead, positioning BMS as a key player in the future of schizophrenia treatment.
